Pub Date : 2025-02-01DOI: 10.1016/j.tibs.2024.12.004
Robert Ahrends , Shane R. Ellis , Steven H.L. Verhelst , Michael R. Kreutz
The brain is an exceptionally lipid-rich organ with a very complex lipid composition. Lipids are central in several neuronal processes, including membrane formation and fusion, myelin packing, and lipid-mediated signal transmission. Lipid diversity is associated with the evolution of higher cognitive abilities in primates, is affected by neuronal activity, and is instrumental for synaptic plasticity, illustrating that lipids are not static components of synaptic membranes. Several lines of evidence suggest that the lipid composition of synapses is unique and distinct from other neuronal subcompartments. Here, we delve into the nascent field of synaptoneurolipidomics, offering an overview of current knowledge on the lipid composition of synaptic junctions and technological advances that will allow us to study the impact on synaptic function.
{"title":"Synaptoneurolipidomics: lipidomics in the study of synaptic function","authors":"Robert Ahrends , Shane R. Ellis , Steven H.L. Verhelst , Michael R. Kreutz","doi":"10.1016/j.tibs.2024.12.004","DOIUrl":"10.1016/j.tibs.2024.12.004","url":null,"abstract":"<div><div>The brain is an exceptionally lipid-rich organ with a very complex lipid composition. Lipids are central in several neuronal processes, including membrane formation and fusion, myelin packing, and lipid-mediated signal transmission. Lipid diversity is associated with the evolution of higher cognitive abilities in primates, is affected by neuronal activity, and is instrumental for synaptic plasticity, illustrating that lipids are not static components of synaptic membranes. Several lines of evidence suggest that the lipid composition of synapses is unique and distinct from other neuronal subcompartments. Here, we delve into the nascent field of synaptoneurolipidomics, offering an overview of current knowledge on the lipid composition of synaptic junctions and technological advances that will allow us to study the impact on synaptic function.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Pages 156-170"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/S0968-0004(25)00014-3
{"title":"Subscription and Copyright Information","authors":"","doi":"10.1016/S0968-0004(25)00014-3","DOIUrl":"10.1016/S0968-0004(25)00014-3","url":null,"abstract":"","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Page e1"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143312908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tibs.2024.11.002
Alicia J. Kowaltowski , Fernando Abdulkader
Oxidative phosphorylation (OxPhos) is the energy-transfer process that generates most of our ATP, fueled by proton and electrical gradients across the inner mitochondrial membrane. A new surprising finding by Hernansanz-Agustín et al. demonstrates that between one-third and half of this gradient is attributable to Na+, transported in exchange for protons within complex I.
氧化磷酸化（OxPhos）是产生大部分 ATP 的能量转移过程，其动力来自线粒体内膜上的质子和电梯度。埃尔南桑斯-阿古斯丁（Hernansanz-Agustín）等人的一项新的惊人发现表明，这种梯度的三分之一到一半可归因于Na+，它在复合体 I 中被输送以交换质子。
{"title":"Textbook oxidative phosphorylation needs to be rewritten","authors":"Alicia J. Kowaltowski , Fernando Abdulkader","doi":"10.1016/j.tibs.2024.11.002","DOIUrl":"10.1016/j.tibs.2024.11.002","url":null,"abstract":"<div><div>Oxidative phosphorylation (OxPhos) is the energy-transfer process that generates most of our ATP, fueled by proton and electrical gradients across the inner mitochondrial membrane. A new surprising finding by <span><span>Hernansanz-Agustín <em>et al</em>.</span><svg><path></path></svg></span> demonstrates that between one-third and half of this gradient is attributable to Na<sup>+</sup>, transported in exchange for protons within complex I.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Pages 87-88"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/S0968-0004(25)00011-8
{"title":"Advisory Board and Contents","authors":"","doi":"10.1016/S0968-0004(25)00011-8","DOIUrl":"10.1016/S0968-0004(25)00011-8","url":null,"abstract":"","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Pages i-ii"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143313389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tibs.2024.11.004
Saugat Pokhrel , Shweta Devi , Jason E. Gestwicki
The molecular chaperones HSP70 and HSP90 play key roles in proteostasis by acting as adapters; they bind to a 'client' protein, often with the assistance of cochaperones, and then recruit additional cochaperones that promote specific fates (e.g., folding or degradation). One family of cochaperones contains a region termed the tetratricopeptide repeat with carboxylate clamps (CC-TPRs) domain. These domains bind to an EEVD motif at the C-termini of cytoplasmic HSP70 and HSP90 proteins, bringing them into proximity to chaperone-bound clients. It has recently become clear that CC-TPR proteins also bind to 'EEVD-like' motifs in non-chaperone proteins, circumventing the need for HSP70s or HSP90s. We provide an overview of the chaperone-dependent and -independent roles of CC-TPR proteins and discuss how, together, they shape proteostasis.
{"title":"Chaperone-dependent and chaperone-independent functions of carboxylate clamp tetratricopeptide repeat (CC-TPR) proteins","authors":"Saugat Pokhrel , Shweta Devi , Jason E. Gestwicki","doi":"10.1016/j.tibs.2024.11.004","DOIUrl":"10.1016/j.tibs.2024.11.004","url":null,"abstract":"<div><div>The molecular chaperones HSP70 and HSP90 play key roles in proteostasis by acting as adapters; they bind to a 'client' protein, often with the assistance of cochaperones, and then recruit additional cochaperones that promote specific fates (e.g., folding or degradation). One family of cochaperones contains a region termed the tetratricopeptide repeat with carboxylate clamps (CC-TPRs) domain. These domains bind to an EEVD motif at the C-termini of cytoplasmic HSP70 and HSP90 proteins, bringing them into proximity to chaperone-bound clients. It has recently become clear that CC-TPR proteins also bind to 'EEVD-like' motifs in non-chaperone proteins, circumventing the need for HSP70s or HSP90s. We provide an overview of the chaperone-dependent and -independent roles of CC-TPR proteins and discuss how, together, they shape proteostasis.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Pages 121-133"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tibs.2024.11.005
Chloé Van Leene , Laura Van Moortel , Karolien De Bosscher , Kris Gevaert
Limited proteolysis coupled to mass spectrometry (LiP-MS) has emerged as a powerful proteomic tool for studying protein conformations. Since its introduction in 2014, LiP-MS has expanded its scope to explore complex biological systems and shed light on disease mechanisms, and has been used for protein drug research. This review discusses the evolution of the technique, recent technical advances, including enhanced protocols and integration of machine learning, and diverse applications across various experimental models. Despite its achievements, challenges in protein extraction and conformotypic peptide identification remain. Ongoing methodological refinements will be crucial to overcome these challenges and enhance the capabilities of the technique. However, LiP-MS offers significant potential for future discoveries in structural proteomics and medical research.
{"title":"Exploring protein conformations with limited proteolysis coupled to mass spectrometry","authors":"Chloé Van Leene , Laura Van Moortel , Karolien De Bosscher , Kris Gevaert","doi":"10.1016/j.tibs.2024.11.005","DOIUrl":"10.1016/j.tibs.2024.11.005","url":null,"abstract":"<div><div>Limited proteolysis coupled to mass spectrometry (LiP-MS) has emerged as a powerful proteomic tool for studying protein conformations. Since its introduction in 2014, LiP-MS has expanded its scope to explore complex biological systems and shed light on disease mechanisms, and has been used for protein drug research. This review discusses the evolution of the technique, recent technical advances, including enhanced protocols and integration of machine learning, and diverse applications across various experimental models. Despite its achievements, challenges in protein extraction and conformotypic peptide identification remain. Ongoing methodological refinements will be crucial to overcome these challenges and enhance the capabilities of the technique. However, LiP-MS offers significant potential for future discoveries in structural proteomics and medical research.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Pages 143-155"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tibs.2024.12.006
Yanfen Liu , Jieyun Bai , Dong Li , Yong Cang
Molecular glue degraders (MGDs) represent a unique class of targeted protein degradation (TPD) modalities. By facilitating protein–protein interactions between E3 ubiquitin ligases and neo-substrates, MGDs offer a novel approach to target previously undruggable or insufficiently drugged disease-causing proteins. Here, we present an overview of recently reported MGDs, highlighting their diverse mechanisms, and we discuss mechanism-based strategies to discover new MGDs and neo-substrates. These strategies include repurposing existing E3 ubiquitin ligase-targeting ligands, screening for novel binders to proteins of interest, and leveraging functional genomics and quantitative proteomics to probe the MGD mechanism of action. Despite their historically serendipitous discovery, MGDs are on their way to being rationally designed to deplete undesired proteins by purposely altering the evolutionarily conserved ligase:substrate interactions.
{"title":"Routes to molecular glue degrader discovery","authors":"Yanfen Liu , Jieyun Bai , Dong Li , Yong Cang","doi":"10.1016/j.tibs.2024.12.006","DOIUrl":"10.1016/j.tibs.2024.12.006","url":null,"abstract":"<div><div>Molecular glue degraders (MGDs) represent a unique class of targeted protein degradation (TPD) modalities. By facilitating protein–protein interactions between E3 ubiquitin ligases and neo-substrates, MGDs offer a novel approach to target previously undruggable or insufficiently drugged disease-causing proteins. Here, we present an overview of recently reported MGDs, highlighting their diverse mechanisms, and we discuss mechanism-based strategies to discover new MGDs and neo-substrates. These strategies include repurposing existing E3 ubiquitin ligase-targeting ligands, screening for novel binders to proteins of interest, and leveraging functional genomics and quantitative proteomics to probe the MGD mechanism of action. Despite their historically serendipitous discovery, MGDs are on their way to being rationally designed to deplete undesired proteins by purposely altering the evolutionarily conserved ligase:substrate interactions.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Pages 134-142"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The Crabtree effect in yeast, where cells prefer fermentation over respiration in high -glucose environments, is associated with mitochondrial repression, but the molecular mechanisms were previously unclear. Recently, Vengayil et al. revealed that knocking out the ubp3 gene, encoding a deubiquitinase enzyme, mitigates the Crabtree effect by increasing mitochondrial phosphate levels.
{"title":"Crabtree effect in yeast: a phosphate tug-of-war between fermentation and respiration","authors":"Ananda Krishnan Manoj , Aswathy Valsalakumari Saradanandan , Vijay Jayaraman","doi":"10.1016/j.tibs.2024.12.001","DOIUrl":"10.1016/j.tibs.2024.12.001","url":null,"abstract":"<div><div>The Crabtree effect in yeast, where cells prefer fermentation over respiration in high -glucose environments, is associated with mitochondrial repression, but the molecular mechanisms were previously unclear. Recently, <span><span>Vengayil <em>et al</em>.</span><svg><path></path></svg></span> revealed that knocking out the ubp3 gene, encoding a deubiquitinase enzyme, mitigates the Crabtree effect by increasing mitochondrial phosphate levels.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Pages 89-91"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tibs.2024.11.006
Hanadi Hoblos , Wayne Cawthorne , André L. Samson , James M. Murphy
Necroptosis is a mode of programmed cell death executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following its activation by the upstream receptor-interacting protein kinase-3 (RIPK3), subsequent to activation of death, Toll-like, and pathogen receptors. The pathway originates in innate immunity, although interest has surged in therapeutically targeting necroptosis owing to its dysregulation in inflammatory diseases. Here, we explore how protein conformation and higher order assembly of the pathway effectors – Z-DNA-binding protein-1 (ZBP1), RIPK1, RIPK3, and MLKL – can be modulated by post-translational modifications, such as phosphorylation, ubiquitylation, and lipidation, and intermolecular interactions to tune activities and modulate necroptotic signaling flux. As molecular level knowledge of cell death signaling grows, we anticipate targeting the conformations of key necrosomal effector proteins will emerge as new avenues for drug development.
{"title":"Protein shapeshifting in necroptotic cell death signaling","authors":"Hanadi Hoblos , Wayne Cawthorne , André L. Samson , James M. Murphy","doi":"10.1016/j.tibs.2024.11.006","DOIUrl":"10.1016/j.tibs.2024.11.006","url":null,"abstract":"<div><div>Necroptosis is a mode of programmed cell death executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following its activation by the upstream receptor-interacting protein kinase-3 (RIPK3), subsequent to activation of death, Toll-like, and pathogen receptors. The pathway originates in innate immunity, although interest has surged in therapeutically targeting necroptosis owing to its dysregulation in inflammatory diseases. Here, we explore how protein conformation and higher order assembly of the pathway effectors – Z-DNA-binding protein-1 (ZBP1), RIPK1, RIPK3, and MLKL – can be modulated by post-translational modifications, such as phosphorylation, ubiquitylation, and lipidation, and intermolecular interactions to tune activities and modulate necroptotic signaling flux. As molecular level knowledge of cell death signaling grows, we anticipate targeting the conformations of key necrosomal effector proteins will emerge as new avenues for drug development.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 2","pages":"Pages 92-105"},"PeriodicalIF":11.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.tibs.2024.10.010
Ella Catherall , Sabina Musial , Nicky Atkinson , Charlotte E. Walker , Luke C.M. Mackinder , Alistair J. McCormick
Pyrenoids are the key component of one of the most abundant biological CO2 concentration mechanisms found in nature. Pyrenoid-based CO2-concentrating mechanisms (pCCMs) are estimated to account for one third of global photosynthetic CO2 capture. Our molecular understanding of how pyrenoids work is based largely on work in the green algae Chlamydomonas reinhardtii. Here, we review recent advances in our fundamental knowledge of the biogenesis, architecture, and function of pyrenoids in Chlamydomonas and ongoing engineering biology efforts to introduce a functional pCCM into chloroplasts of vascular plants, which, if successful, has the potential to enhance crop productivity and resilience to climate change.
{"title":"From algae to plants: understanding pyrenoid-based CO2-concentrating mechanisms","authors":"Ella Catherall , Sabina Musial , Nicky Atkinson , Charlotte E. Walker , Luke C.M. Mackinder , Alistair J. McCormick","doi":"10.1016/j.tibs.2024.10.010","DOIUrl":"10.1016/j.tibs.2024.10.010","url":null,"abstract":"<div><div>Pyrenoids are the key component of one of the most abundant biological CO<sub>2</sub> concentration mechanisms found in nature. Pyrenoid-based CO<sub>2</sub>-concentrating mechanisms (pCCMs) are estimated to account for one third of global photosynthetic CO<sub>2</sub> capture. Our molecular understanding of how pyrenoids work is based largely on work in the green algae <em>Chlamydomonas reinhardtii</em>. Here, we review recent advances in our fundamental knowledge of the biogenesis, architecture, and function of pyrenoids in <em>Chlamydomonas</em> and ongoing engineering biology efforts to introduce a functional pCCM into chloroplasts of vascular plants, which, if successful, has the potential to enhance crop productivity and resilience to climate change.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"50 1","pages":"Pages 33-45"},"PeriodicalIF":11.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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